eIF4B phosphorylation by Pim kinases plays a critical role in cellular transformation by Abl oncogenes----中国科学院微生物研究所

科研成果

论文题目:	eIF4B phosphorylation by Pim kinases plays a critical role in cellular transformation by Abl oncogenes
作者:	Yang Jianling, Wang Jun, Chen Ke, Guo Guijie, Xi Ruijiao, Rothman Paul B, Whitten Douglas, Zhang Lianfeng, Huang Shile, Chen Ji-Long
联系作者:	Chen Ji-Long
刊物名称:	Cancer Research
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年份:	2013
影响因子:	8.164
论文下载:	http://cancerres.aacrjournals.org/content/early/2013/06/07/0008-5472.CAN-12-4277.abstract
摘要:	Alterations in translation occur in cancer cells but the precise pathogenic processes and mechanistic underpinnings are not well understood. In this study, we report that interactions between Pim family kinases and the translation initiation factor eIF4B are critical for Abl oncogenicity. Pim kinases Pim-1 and Pim-2 both directly phosphorylated eIF4B on Ser406 and Ser422. Phosphorylation of eIF4B on Ser422 was highly sensitive to pharmacological or RNAi-mediated inhibition of Pim kinases. Expression and phosphorylation of eIF4B relied upon Abl kinase activity in both v-Abl- and Bcr-Abl-expressing leukemic cells, based on their blockade by the Abl kinase inhibitor imatinib. Ectopic expression of phosphomimetic mutants of eIF4B conferred resistance to apoptosis by the Pim kinase inhibitor SMI-4a in Abl-transformed cells. In contrast, silencing eIF4B sensitized Abl transformed cells to imatinib-induced apoptosis and also inhibited their growth as engrafted tumors in nude mice. Extending these observations, we found that primary bone marrow cells derived from eIF4B-knockdown transgenic mice were less susceptible to Abl transformation, relative to cells from wild-type mice. Taken together, our results identify eIF4B as a critical substrate of Pim kinases in mediating the activity of Abl oncogenes, and they highlight eIF4B as a candidate therapeutic target for treatment of Abl-induced cancers.